A novel syndrome of cerebral cavernous malformation and Greig cephalopolysyndactyly

Laboratory investigation

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Object

Greig cephalopolysyndactyly syndrome (GCPS) is one of a spectrum of overlapping clinical syndromes resulting from mutations in the gene GLI3 on chromosome 7p. Cerebral cavernous malformation (CCM) is caused by mutations in three distinct genes, including Malcavernin (CCM2), which also maps to chromosome 7p and is located 2.8 Mbp from GLI3. The authors describe a new syndrome that combines the vascular lesions characteristic of CCM with the hallmarks of GCPS, including polydactyly, hypertelorism, and developmental delay.

Methods

The authors used high-resolution array-based comparative genome hybridization (CGH) analysis to characterize the 3 million–bp deletion on chromosome 7 that accounts for this novel clinical presentation. A 4-year-old girl presented with polydactyly, hypertelorism, and developmental delay and was also found to have multiple CCMs after suffering a seizure.

Results

Genetic analysis using array-based CGH revealed a deletion affecting multiple genes in the 7p14-13 locus, the interval that includes both CCM2 and GLI3. Quantitative real-time polymerase chain reaction (RT-PCR) on genomic DNA confirmed this genomic lesion.

Conclusions

A novel syndrome, combining features of CCM and GCPS, can be added to the group of entities that result from deleterious genetic variants involving GLI3, including GCPS, acrocallosal syndrome, Pallister–Hall syndrome, and contiguous gene syndrome. The deletion responsible for this new entity can be easily detected using either array-based chromosomal analysis or quantitative RT-PCR.

Abbreviations used in this paper:CCM = cerebral cavernous malformation; CGH = comparative genome hybridization; CNV = copy number variant; GCPS = Greig cephalopolysyndactyly syndrome; MR = magnetic resonance; RT-PCR = real-time polymerase chain reaction.

Article Information

Address correspondence to: Murat Gunel, M.D., Department of Neurosurgery, Yale University School of Medicine, 333 Cedar Street, Tompkins 4, New Haven, Connecticut 06510. email: murat.gunel@yale.edu.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    Radiographs obtained in a 32-month-old girl, demonstrating bilateral polysyndactyly of the great toes (A) and scoliosis of the spine (B). Serial axial T1- (C) and T2-weighted (D) MR images obtained in the patient at 4 years of age, revealing subcortical CCMs (arrows) in the right parietal and left frontal lobes as well as a left periventricular CCM. Reformatted MR image (E) showing a normal central sulcus on the left side (arrow) and an asymmetrically formed central sulcus on the right.

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    Graphs depicting the results of CNV analysis. On chromosome 7, a deletion was revealed within the CCM2 locus (A, arrowhead), but no apparent CNVs within the CCM1 locus (arrow). With this analysis, gene deletions are represented by negative log2 ratios of the signal intensity relative to normal. To be significant, the log2 ratio (y axis) must be less than −0.3. The log2 ratio at the CCM2 region is less than −0.5, indicating the presence of a deletion in that locus. There is no CNV within the CCM3 locus (B). Bar graphs of quantitative RT-PCR of CCM2 (C) and GLI3 (D) showing approximately half of the relative amplification of each respective gene amplicon, consistent with the presence of a heterozygous deletion in the affected patient (2222-1) within the CNV interval. The controls and parents (father 2222-2 and mother 2222-3) demonstrate full amplification of each respective gene amplicon.

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